The present invention is directed to certain racemic and optically active pyrido[1,2-a]pyrazine derivatives, as defined by the formula (I) below, which are useful as antidepressants and as anxiolytic agents; and to intermediates therefor, as defined by the formulas (II) and (III), below.
Anxiety and depression are common afflictions which adversely affect a significant portion of the human population. These afflictions are frequently found in association in the same individual. It has been known for many years that the symptoms of anxiety in human subjects can often be alleviated by the administration of certain chemical substances, which in this context are called antianxiety agents, or anxiolytics. In modern medical practice, a widely-used class of anxiolytics is the benzodiazepines, such as diazepam, but these products suffer certain disadvantageous properties such as undesired sedative activity. More recently a number of 1-(2-pyrimidinyl)-4-[4-(cyclic-imido)butyl]piperidine derivatives have been disclosed as anxiolytic agents which are generally lacking such sedative activity. Among these are busipirone, where the cyclic-imido group is 4,4-tetramethylene-piperidine-2,6-dion-1-yl (Wu et al., U.S. Pat. Nos. 3,717,634 and 3,907,801; Casten et al., U.S. Pat. No. 4,182,763); gepirone, where the group is 4,4-dimethylpiperidine-2,6-dion-1-yl (Temple, Jr., U.S. Pat. No. 4,423,049); and ipsapirone, where the group is 1,1-dioxobenzo[d]isothiazol-3(2H)-on-2-yl (Dompert et al., German patent publication 3,321,969-A1). See also Ishizumi et al., U.S. Pat. Nos. 4,507,303 and 4,543,355; Freed et al., U.S. Pat. No. 4,562,255; Stack et al., U.S. Pat. No. 4,732,983; and New et al., U.S. Pat. No. 4,524,026.
Such agents as busipirone and gepirone have now been shown to possess antidepressant activity. See for example, Schweizer et al., Psychopharm. Bull., v. 22, pp. 183-185 (1986), and Amsterdam et al., Current. Therap. Res., v. 41, pp. 185-193 (1987). See also Stack, U.S. Pat. No. 4,788,290 describing certain 2-pyrimidinylpiperazine derivatives as having combined anxiolytic and antidepressant activity.
The present bis-aza-bicyclic compounds generally show minimal in vivo stimulation of dopaminergic systems, reflective of reduced or minimal neurological side effects in the clinical use of these compounds.